T cell acute lymphoblastic leukemia (T-ALL) is a disease induced by the transformation of T cell progenitors. It mainly afflicts children and adolescents. Although treatment outcome in T-ALL has improved in recent years, patients with relapsed disease continue to have dismal prognosis despite the use of protocols involving hematopoietic stem cell transplantation. T-ALL patients present at diagnosis with elevated white cell counts, hepatosplenomegaly, and are at elevated risk for central nervous system (CNS) relapse. For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The dramatic increase in survival is thought to be worth the significant side effects associated with this therapy. Such complications include secondary tumors, neurocognitive deficits, endocrine disorders and growth impairment. Little is known about the mechanism of leukemic cell infiltration of the CNS despite its clinical significance. Here, we show using T-ALL animal modeling and gene-expression profiling that the chemokine receptor CCR7 is the essential adhesion signal required for the targeting of leukemic T-cells into the CNS. CCR7 gene expression is controlled by the activity of the T- ALL oncogene Notch1, the most central oncogene in this disease, and is expressed in human tumors carrying Notch1 activating mutations. Silencing of either CCR7 or its chemokine ligands in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, CNS targeting by human T-ALL cells depends on their ability to express CCR7. All these observations made us hypothesize that the CCR7 chemokine receptor and its ligands are potent regulator of leukemic cell migration/tissue infiltration in response to oncogenic Notch1 signaling. This hypothesis is tested in this application. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS targeted therapy, thus reducing short- and long-term complications of therapy. PUBLIC HEALTH RELEVANCE: T cell acute lymphoblastic leukemia (T-ALL) is a deadly blood tumor that afflicts mainly children. One of the devastating manifestations of the disease is infiltration of leukemic T cells in to the central nervous system (CNS) that can cause neural tissue damage and paralysis. In this application we study the mechanism of CNS entry and propose novel targets for future therapy.